Etiology: Finding the Causes
Identifying and understanding the factors that lead to breast cancer in individual women and in the population as a whole is crucial. Through this work, we can learn how to prevent breast cancer, for example, by discovering causative factors that can then be eliminated or reduced, or by identifying conditions that predispose a person to breast cancer and for which there may be compensating treatments.
Research Conclusions
A one-year study looking at genetic factors that might influence breast cancer risk was Vitamin D & Genetics of Vitamin D Receptor in Breast Cancer conducted by Dr. Sue A. Ingles, at the University of Southern California. Dr. Ingles questioned whether genetic variations in the Vitamin D receptor (VDR) are related to breast cancer incidence. (It has been speculated that variations in the VDR gene might affect breast cancer in a manner similar to the way it is known to affect bone mineral density.) Preliminary results indicate that women with a high-risk VDR genotype may be at a 3-10 fold increased risk of breast cancer compared to women with a low-risk genotype. It is suspected that the risk is affected directly or indirectly by the gene's influence on Vitamin D status, and further work on this issue is ongoing in another CBCRP grant in the third cycle.
A second study, Genetic Susceptibility to Breast Cancer, conducted by Dr. Brian Henderson, at the University of Southern California, obtained preliminary data that support an important association between the CYP17 gene and breast cancer risk. This gene encodes an enzyme that functions at key points during the synthesis of estrogens in the ovaries. It contains a polymorphism, or change in the DNA sequence, which results in two alleles, designated A1 & A2. Thus, there are three different combinations of the gene that a woman can have: A1/A1, A1/A2 or A2/A2. Dr. Henderson found an increased risk of advanced breast cancer in women who carried the A1/A2 or A2/A2 form of the CYP17 gene. A2 women were two and one-half times more likely to have advanced breast cancer than A1/A1 women. It was also found that CYP17 is associated with age at menarche (the age when a woman first starts ovulating and having menstrual periods). The importance of these findings is twofold: 1) the CYP 17 A2 forms may play a role in as much as 30% of all breast cancer, and 2) the three forms of the CYP 17 gene (i.e., the "genotype") may be an important marker for the onset of ovulation and the establishment of regular ovulatory cycles (which may be the most critical reproductive determinant of breast cancer risk). A colleague of Dr. Henderson's has received CBCRP funds for another project to verify these findings, and to look for possible differences in the distribution of these alleles among groups of ethnically diverse women.
Dr. Shelley M. Enger at the University of Southern California, conducted a two-year study (Alcohol and Risk of Estrogen-Receptor Positive Breast Cancer) to investigate whether the relationship of alcohol consumption and risk of breast cancer is distinct between women with estrogen-receptor positive (ER+) and those with estrogen-receptor negative (ER-) tumors. She found that consumption of 27 grams of alcohol per day (approximately 2 or more drinks) was associated with an increased risk of ER+ and PR+ breast cancer and that alcohol intake is related only to hormone-receptor positive tumors, supporting an estrogen-mediated effect of alcohol on the development of breast cancer. And although the issue is not yet resolved, fairly substantial epidemiologic and clinical evidence suggests that hormone-receptor status defines distinct tumor types, and her findings provide further support for this hypothesis.
Bovine Leukemia Virus and Human Breast Cancer Risk. Dr. Gertrude Buehring of the University of California, Berkeley completed a 1-year IDEA project in which she found evidence that human samples (breast biopsy/blood serum) showed the possibility of a prior infection with a virus, Bovine Leukemia Virus (BLV). A similar virus is known to cause breast cancer in mice. Although there is no present evidence that BLV directly causes human breast cancer, the precise risk that may be associated with the consumption of undercooked beef or unpasteurized dairy product has not been rigorously determined. Dr. Buehring's lab has additional CBCRP funding to explore this topic in more detail using the methods of molecular biology. The potential of foreign infectious agents to cause human disease is of interest, and represents a highly novel approach in searching for the potential environmental causes of and/or risks associated with human breast cancer.
Dr. Nicole M. Probst-Hensch of the USC/Norris Comprehensive Cancer Center, in a one-year study of women of different ethnic backgrounds (Breast Cancer and Genetic Differences in Estrogen Formation), looked into the question of whether postmenopausal women differ genetically in how efficiently their aromatase enzyme produces estrogens, and whether such differences affect breast cancer risk. (Aromatase is the protein most relevant for estrogen production in humans and is the rate-limiting step in converting the androgen androstenedione to estrogen.) She looked at two variations (polymorphisms) of the gene for aromatase, and found that genetic variation at either of the two known loci does not appear to directly influence the efficiency with which aromatase converts precursor hormones into estrogens. Other work (in a very small sample) showed that, while African-American women had higher concentrations of androstenedione hormones in the blood than Latina women, Latina women produced estrogens more efficiently for any given amount of androstenedione than African-American or White women.
This suggests that other, as yet unknown, variations may be responsible for the obscured differences. However, these potential differences in aromatase activity do not correlate with the differences in postmenopausal breast cancer risk of these ethnic groups. Her work is important given that medications that specifically inhibit aromatase function in the breast are currently being developed. Therefore, her work needs to be followed up to establish whether differences in the androstenedione to estrone ratio reflect genetic variation in the aromatase gene at loci other than the two already studied, and whether they are of relevance to breast cancer risk, and to confirm whether elevated local or systemic aromatase activity exists in a subgroup of woman who could potentially benefit from preventive treatment with aromatase inhibitors.
Environment and gene/environment interactions: nature and nurture
Several CBCRP projects were funded to identify and characterize agents that could cause or contribute to the development of breast cancer.Dr. Moire R. Creek of SRI International is investigating whether xenoestrogens (environmental estrogens) can cause DNA damage to breast cells. She is finding that the status of the estrogen receptor in the cells may influence the amount of detectable DNA damage. Dr. Regine Goth-Goldstein at Lawrence Berkeley National Laboratory is looking at breast cancer susceptibility by concentrating on two enzymes, one that activates (CYP1A1) and the other that detoxifies (GSTM1) carcinogens called polycyclic aromatic hydrocarbons. She finds a trend, which is not yet statistically significant, of a higher percentage of breast cancer patients lacking the detoxifying gene.
Some proteins can serve as predictors of breast cancer development and progression. Understanding how known markers function in normal and tumor cells and identifying new markers can provide us with ideas regarding what aspects of cell growth and development should be targeted for therapy. Dr. Donna Williams-Hill of the University of Southern California is investigating the role of tumor suppressor gene expression during different stages of rat mammary gland development in conveying breast cancer susceptibility. Dr. Williams-Hill has shown that BRCA1 protein levels are lowest in the mammary gland of 3-week old rats and increase gradually as the rat ages to 5 weeks (pre-puberty) and 8 weeks (puberty). Continued experiments will determine whether susceptibility to carcinogen exposure correlates with BRCA1 levels.
Hormones and nutrition: understanding the modern woman's lifestyle
Recently an additional form of the estrogen receptor (ER) was discovered and named ERb. Dr. Peter Kushner of the University of California, San Francisco has found that ERb signals in opposite ways from the traditional ER (ERa) when bound with AP-1 and 17a-estradiol: ERa turns on genes and ERb turns off genes. However, the interaction of the antiestrogens tamoxifen, raloxifene, and ICI 164384 with ERb at an AP1 site turns genes on. Thus, an increase in the population of ERb may be responsible for the development of antiestrogen resistance.
Dr. James Felton of Lawrence Livermore National Laboratory is looking at the metabolism of PhIP, a carcinogen that can be generated by cooked meats. He is developing a method to detect the PhIP metabolites in human urine after having successfully detected them in rat urine. The ultimate goal of this project is determine the metabolite profile that is associated with DNA adduct formation and breast cancer susceptibility.
Recently Initiated Research
In 1997, CBCRP awarded 14 new grants to investigate possible causes of breast cancer, including exploration of various pesticides, gene/environment interactions, detection of a viral infection contracted through cows, and exposures of flight attendants. For example, one study is exploring the interaction between genetic variation in how certain toxins are handled by the body and breast cancer risk. The results should make a significant contribution to the current knowledge about possible environmental causes of breast cancer. Other studies are examining the possible link between breast cancer and various environmental factors, including radiation, ozone, and viruses.
